This renewal application builds on themes of our previous studies mechanistically defining & therapeutically targeting pathways driving castration-resistant prostate cancer (CRPC) progression. CRPC is attributed to re-activation of the androgen-receptor (AR) axis along with stress-activated cytoprotective chaperone and growth factor signaling pathways. With new potent AR pathway inhibitors like MDV3100 and abiraterone (ABI) approved in CRPC, emergence of resistance to these agents represents the next major clinical challenge. Recently, we identified activation of the Semaphorin 3C (SEMA3C) signaling pathway in CRPC and post-MDV3100 recurrent tumors. SEMA3C is a secreted growth factor associated with cancer metastasis and chemoresistance that we found associated with PTEN loss, clusterin over-expression, and regulation of AR protein levels and transcriptional activity. These findings link SEMA3C with PTEN loss and increased AKT & AR activity, 2 key pathways driving CRPC and MDVS100 treatment resistance. SEMA3C enhances PCa cell survival under castrate conditions, and we have developed 2 novel SEMA3C inhibitors that delay CRPC progression. Our overall aim is to define mechanisms of SEMA3C in promoting resistance to castration and MDVS100 therapies, and to develop preclinical mechanistic and anti-cancer activity data to support a first-in-man clinical trial of a novel SEMA3C inhibitor in CRPC. Aim 1 will define changes in SEMA3C signaling pathway in CRPC and after treatment with MDVS100 or ABI in LNCaP or LUCaP35CR models, respectively. Aim 2 will characterize the functional role of SEMA3C on MDVS100 treatment resistance and define cross-talk between SEMA3C signaling and AR activity in MDVS100 sensitive vs. refractory CRPC. Aim 3 will test in vivo activity of novel SEMA3C fusion protein and antisense inhibitors in preclinical models of CRPC as A) monotherapy; and B) in combination with i) MDVS100; ii) docetaxel, and iii) inhibitors of AR chaperone proteins Hsp27 (OGX-427), or Hsp90 (PF-04928473). The bench to bedside Aim 4 will conduct a Phase l/II clinical trial of SEMA3C soma domain (SD) Fc fusion protein inhibitor in men with CRPC and examine the utility of serum SEMA3C as a clinical biomarker.